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PubMed1998

A newly discovered function for C1 inhibitor, removal of the entire C1qr2s2 complex from immobilized human IgG subclasses.

A new function for C1 inhibitor (C1 INH) is reported. C1 inhibitor dislodged the entire activated C1 complex (C1qr2s2) from immobilized human IgG. C1 binding to doses of immobilized human IgG3, IgG1, or IgG2 was quantified as a function of time. When human serum, as a source of C1qr2s2, was added to relatively low doses of immobilized IgG, C1q binding peaked at 1.0 min then gradually decreased. However when purified C1q was applied to immobilized IgG, C1q binding did not diminish with time. The removal of C1q was duplicated by adding purified C1 INH to C1qr2s2 which had been bound to immobilized IgG. The dislodgement of C1q from immobilized IgG required the presence of intact C1qr2s2 and of C1 INH. This removal of C1q by purified C1 INH was prevented when activated C1s was used to neutralize C1 INH function or when relatively high levels of IgG were immobilized.

Binding, Competitive↗
PubMed1993

Autoimmune C1 inhibitor deficiency: report of eight patients.

PURPOSE: In this study, we investigated the clinical and biochemical features and the responses to treatment of eight patients with auto-antibody-mediated C1 inhibitor (C1-INH) deficiency and symptoms of angioedema. PATIENTS AND METHODS: In addition to the 8 patients with acquired angioedema (AAE), we also studied 36 subjects with hereditary angioedema (HAE), 15 of them treated with C1-INH plasma concentrate, and 26 patients with different autoantibodies in their plasma (10 with systemic lupus erythematosus, 6 with lupus-like anticoagulant, and 10 with chronic liver disease). Functional C1-INH was measured with the reagent kit of Immuno (Vienna, Austria); C1-INH, C4, and C1q antigen were determined by radial immunodiffusion; and autoantibodies to C1-INH were detected by an enzyme-linked immunosorbent assay method. RESULTS: Four patients with AAE had no other diseases, one had breast cancer, one liver hydatidosis, one Waldenström's disease, and one a benign M component. Functional C1-INH levels were below 30% of normal, and C1q plasma levels were low in seven patients but normal in one. Autoantibodies to C1-INH were detectable in all eight AAE patients but in none of the others. Prophylactic treatment with attenuated androgens was successful in one of four patients, and with antifibrinolytic agents (tranexamic acid) in six of seven patients. Laryngeal attacks in five patients were treated with C1-INH plasma concentrate; two patients had marked clinical and biochemical responses. In three, the symptoms resolved only with high doses, and the biochemical parameters did not significantly increase. CONCLUSIONS: Our results suggest that patients with autoimmune AAE are clinically and biochemically heterogeneous. They have different responses to treatment that seem to be related to variable C1-INH consumption.

Aged↗
PubMed1983

A new simple method for determination of C1-esterase inhibitor activity in plasma.

A convenient method for the determination of C1-esterase inhibitor activity in plasma samples is described. The method is based on addition of purified C1s to plasma and measuring excess C1s with a new chromogenic tripeptide-p-nitroanilide substrate with a recording spectrophotometer. Addition of C1s to C1-esterase inhibitor-depleted plasma did not result in any appreciable inactivation of the enzyme for three hours. The concentration of C1-esterase inhibitor in 19 healthy individuals was estimated as 1.63 +/- 0.27 (SD) mumol/l. The correlation with C1-esterase inhibitor antigen in these individuals and 19 patients with varying concentrations of C1-esterase inhibitor was excellent. The correlation with an antikallikrein assay was found to be poor.

Complement Activating Enzymes↗
PubMed1980

Hereditary angioneurotic edema: immunochemical 'activity' without clinical expression.

An 11-year-old white female with focal glomerulonephritis was found to have an absence of functional C1 esterase inhibitor. C1 esterase inhibitor measured by immunochemical means, however, was only slightly reduced. After an initial time period marked by variable hypocomplementemia, presumably due to immune complex formation associated with the nephritis, immunochemical signs of active and severe hereditary angioneurotic edema (HANE) developed. These have been unremitting for 3 1/2 years. Clinical signs of HANE, however, have never developed. Thus, during this time, there have been no clinical abnormalities despite the fact that free C1 esterase activity has been persistently present in this patient's serum and serum levels of functional C1 esterase inhibitor, C2 and C4 have been continuously less than 2% of normal. It appears, therefore, that this patient has an unusual form of HANE mainifested solely by the complement alterations seen during symptomatic attacks but without clinical expression of that serologic activity.

Angioedema↗
PubMed1997

Activation of the coagulation cascade in C1-inhibitor deficiencies.

Activation of the contact and complement systems in C1-inhibitor deficiencies is thought to contribute to the pathogenesis of angioedema attacks by releasing kinins. Trigger stimuli of attacks may also activate coagulation. This is particularly important because experimental data suggest that thrombin, the main enzyme of the coagulation cascade, increases vascular permeability and can thus influence edema formation. We have studied 19 patients with hereditary angioedema (HAE) during remission, 5 HAE patients during acute attacks, and 6 patients with acquired angioedema (AAE) during remission and during seven attacks. Thirty normal subjects, matched for sex and age, served as controls. Generation of thrombin was measured by enzyme-linked immunosorbent assay (ELISA) as plasma levels of the prothrombin fragment 1 + 2 (F1 + 2); the initiators of the tissue factor and contact coagulation pathways were investigated by measuring plasma levels of activated factor VII (FVIIa) coagulometrically and activated factor XII (FXIIa) by ELISA. Cleavage of high molecular weight kininogen (HK) was evaluated by immunoblotting analysis. F1 + 2 was slightly increased during remission and further significantly increased during attacks in both HAE (P = .0115) and AAE. FVIIa and FXIIa, normal during remission, increased strikingly during attacks in both HAE (P = .0022 and P = .0044) and AAE. During remission, cleaved HK was normal in HAE and high in AAE; during attacks it increased in HAE (P = .0008) and remained elevated in AAE. Our data indicate that in C1-inhibitor deficient patients there is increased generation of thrombin during attacks, with signs of activation of both the contact and tissue factor coagulation pathways. In conclusion, C1-inhibitor deficiency, whether hereditary or acquired, has demonstrable activation of the coagulation and kinin-forming cascades during attacks and that thrombin should be considered a possible contributing factor in the pathogenesis of edema in HAE and AAE.

Adult↗
PubMed1995

Levels of the terminal complement complex, C3a-desArg and C1-inhibitor in adult patients with capillary leak syndrome following bone marrow transplantation.

Capillary leak syndrome (CLS) is a severe complication after bone marrow transplantation (BMT). To investigate whether there is a pathogenetic role of the complement system, we monitored the levels of the terminal complement complex C5b-9 (TCC) and C3a-desArg as indicators of an activation of the complement system and the inhibitor of the classical pathway of the complement cascade, C1 inhibitor (C1-INH), in 48 bone marrow transplant recipients from 1 week before to 5 weeks after transplantation. Capillary leak syndrome developed in 7 out of 48 patients between days 1 and 12 after BMT. Complement activation as indicated by TCC levels was more pronounced in patients with CLS (n = 7) from day -8 to +28 (p < 0.05; day -1) and the elevation of TCC levels lasted longer in CLS patients (peak day 21) than in patients without this complication (peak day 7). Mean C3a-desArg levels were highest in patients with CLS reaching a peak at day 7. During the early posttransplant period a significant elevation of C1-INH levels (p < 0.01 and p < 0.05 respectively) compared with baseline levels (day -8) was found in patients with and without CLS, which was more pronounced in those patients with CLS (p < 0.05). Although we could not observe an absolute C1-INH deficiency as compared to healthy individuals our data support the presence of a relative deficiency of the inhibitor which might explain the reported beneficial effects of C1-INH substitution in BMT related CLS.

Adult↗
PubMed2004

Antigen localization within the splenic marginal zone restores humoral immune response and IgG class switch in complement C4-deficient mice.

Defects of early complement components (C1, C4 and C2) are associated with the development of systemic lupus erythematosus (SLE). The availability of complement knockout mice has increased our knowledge on the role of complement in the regulation of adaptive immunity. An impaired removal of apoptotic bodies, a disturbed clearance of IgG immune complexes (ICs) and an insufficient B-cell regulation via complement receptors CD21/CD35 have been discussed as explanations for the induction of autoimmunity; however, a unifying hypothesis for the loss of B-cell tolerance in the absence of C1 or C4 is still lacking. Using IgM-containing ICs, we observed a significant accumulation of antigen within the splenic marginal zone (MZ) of C4-deficient mice but not in C3-deficient or complement receptors CD21/CD35-deficient mice. The targeting of antigen toward the MZ restored adaptive immunity (antibody response and class switch) in C4-deficient animals. A new explanation for the association of SLE and complement C4 deficiency would be that in the absence of C4, natural antibodies (IgM type) localize more self-antigen toward the MZ so that the auto-antibody response is increased and autoimmune disease ensues. As such, an inadequate localization of self-antigens might be responsible for the annulment of peripheral B-cell tolerance in the absence of C4.

Animals↗
PubMed1977

Purification and some properties of rabbit C1 inactivator.

C1 inactivator (C1 INA) was highly purified from rabbit serum. C1 INA thus purified was a single polypeptide chain with a molecular weight of 105,000 or 140,000, as estimated by SDS-polyacrylamide gel electrophoresis or gel filtration on Sephadex G-200, respectively. It inhibited rabbit and also human C1, when the C1 activities were measured in terms of hydrolyses of acetylglycyl-L-lysine methylester, N-alpha-acetyl-L-arginine methylester and N-alpha-acetyl-L-tyrosine ethylester. These properties showed that rabbit C1 INA bears a marked structural similarity to human C1 INA. Furthermore, rabbit C1 INA was capable of inhibiting similarly both rabbit C1s and its active fragment lacking a half of the H chain of C1s, indicating that deletion of a half of the H chain did not affect the susceptibility of C1s to the inhibitory activity of C1 INA.

Animals↗
PubMed1991

[Hereditary angioedema].

Hereditary angioedema is a rare disease, transmitted as an autosomal dominant trait. The disease usually manifests as acute subcutaneous or submucosal swellings and abdominal pain of two to five days duration. When localised to head or throat life-threatening edema of the larynx may occur. The disease is caused by reduced amount of active C1 inhibitor. The edema is not due to an allergic reaction and medication for such is of little or no value. Profylactic medication may be given when the attacks are frequent and ought to be given before dental extractions, intubation of the larynx, major surgery especially of the oropharynx, and births. The acute attack is best treated by intravenous injection of C1 inhibitor concentrate.

Angioedema↗
PubMed1986

Study of the effect of high molecular weight kininogen upon the fluid-phase inactivation of kallikrein by C1 inhibitor.

Plasma kallikrein and factor XIa circulate bound to high molecular weight kininogen, and such binding has been reported to protect these enzymes from inactivation by their respective inhibitors. However, this observation is controversial, and the effect of high molecular weight kininogen upon the interaction between kallikrein and C1 inhibitor (C1-INH) has been questioned. We have re-evaluated this reaction and studied the rate of inhibition of kallikrein by C1-INH in the presence and absence of high molecular weight kininogen. The second-order rate constant of inhibition of kallikrein by C1-INH was unaffected by saturating concentrations of high molecular weight kininogen. Our results suggest that although high molecular weight kininogen clearly augments the rate of formation of kallikrein and other enzymes of the contact activation pathway, it has no effect on the rate of enzyme inhibition by C1-INH.

Complement C1 Inactivator Proteins↗
PubMed1995

Improved method for measuring C1-r-C1-s-(C1 inh)2 complexes by an enzyme-linked immunosorbent assay.

Measurement of C1-r-C1-s-(C1 inh)2 complexes in serum or plasma by enzyme-linked immunosorbent assay (ELISA) has been proposed as a relatively convenient and sensitive means for assessing C1 activation. However, interference by unactivated C1q (r-s)2 at low serum or plasma dilutions has resulted in estimates that vary widely with the degree of serum or plasma dilution. Precipitating the interfering C1q (r-s)2 with 6% polyethylene glycol has been proposed to resolve this problem, but here it is shown that this procedure also precipitates or coprecipitates some of the C1-r-C1-s-(C1 inh)2 complexes. Satisfactory results have been achieved without PEG precipitation by testing high plasma dilutions under conditions where there is a sufficient excess of anti-C1s coating the microtitration plate wells that removal of C1q (r-s)2 is not necessary. Optimizing conditions for quantitating these complexes at high dilution have been investigated. The mean normal EDTA plasma C1-r-C1-s-(C1 inh)2 complex measurement was 36.6 +/- 7.0 (S.D.) ELISA units with a 95% confidence interval of 19.5-47.6u. Besides providing a sensitive assay for C1 activation, measuring C1-r-C1-s-(C1 inh)2 complexes may help to clarify the pathophysiologic mechanisms resulting from C1 inh deficiency under various conditions.

Adult↗
PubMed1991

[Angioneurotic edema in hereditary alpha-1-antitrypsin deficiency].

A young man with angioedema presented with normal concentration and function of C1-esterase inhibitor, but with a hereditary deficiency of alpha-1 antitrypsin (Pi-ZZ type). The pathogenetic relevance of this defect is discussed with respect to the partial deficiency of the complement component C4 (C4BQ0), which was found in addition.

Adult↗
PubMed1991

[Hereditary angioneurotic edema. Recent progress in diagnosis and treatment. Importance of a national registry].

The hereditary angioneurotic oedema is an exceptional disease of deadly risk from glottic oedema. The diagnosis is based on a very low serum C4, with collapsed C1 INH for a patient who has repeated attacks of Quincke's oedema or pseudo occlusive digestive crisis. These crisis are prevented by taking anabolic steroids and must be treated when they are serious by intravenous C1 INH. The recent contributions of the immunogenetic and the interest of a national registry are underlined.

Angioedema↗
PubMed1997

Secreted chondroitin sulfate proteoglycan of human B cell lines binds to the complement protein C1q and inhibits complex formation of C1.

We recently characterized a species of proteochondroitin sulfate (CSPG) secreted by human B cell lines that closely resembles in its structure the serum-derived C1q inhibitor (C1qI). These proteoglycans have in common a molecular mass of approximately 130 to 150 kDa with a core protein of 30 kDa to which up to four chondroitin sulfate chains each of approximately 26 kDa are attached. Since this B cell-derived CSPG is a potential source for serum C1qI, we measured its capacity to interact with C1q in solid-phase binding and complex electrophoresis assays. B cell CSPG purified from culture supernatants of the two human B cell lines JOK-1 and U266 strongly bound to C1q. In contrast to the secreted form, cellular proteoglycan of the myeloma cell line U266 did not interact with C1q. Binding of C1q to CSPG was competitively inhibited by free glycosaminoglycans (GAG) in the order dextran sulfate > heparin > heparan sulfate > chondroitin-6-sulfate (CS-C) > dermatan sulfate (CS-B) > chondroitin-4-sulfate (CS-A). B cell CSPG inhibited the hemolytic activity of C1q and C1. In addition, B cell CSPG blocked C1q receptor binding in a dose-dependent manner. The proteoglycans did not influence the activity of C1 complex already bound to EAC4 target cells. By interaction of CSPG with solid-phase-bound C1q, formation of the C1 complex upon the addition of C1r and C1s was impaired. Strong binding of B cell CSPG to C1q, its inhibition of C1q activity, and its structural similarities to the previously described human serum C1qI indicate that B cells produce a soluble CSPG, which may act as C1qI under physiologic conditions.

B-Lymphocytes↗
PubMed1998

Acquired angio-oedema caused by IgA paraprotein.

The syndrome of acquired angio-oedema is characterized by late onset of recurrent bouts of angio-oedema or abdominal pain and may be caused by an acquired deficiency of C1-inhibitor (C1-INH), the inhibitor of the first component of complement. Acquired C1-INH deficiency has been described in approximately 50 patients and is strongly associated with malignant B-cell proliferations. We describe a patient with an 8-year history of recurrent abdominal symptoms and angio-oedema with acquired C1-INH deficiency, caused by the presence of IgA-kappa antibodies that inactivate C1-INH. Analysis of the bone marrow revealed an IgA-kappa monoclonal population of plasma cells, without evidence of overt myeloma. Angio-oedema caused by an autoantibody of the IgA isotype is extremely rare and has never been described in a Dutch patient. Recognition of angio-oedema, both hereditary and acquired, is important because of the therapeutic consequences, as will be discussed.

Abdominal Pain↗
PubMed2001

A review of the reported defects in the human C1 esterase inhibitor gene producing hereditary angioedema including four new mutations.

C1 esterase inhibitor (C1INH) is an important regulatory protein of the classical pathway of complement. Mutations in the gene for this protein cause the autosomal dominant disorder hereditary angioedema (HAE). Approximately 85% of patients with HAE have a Type I defect, characterized by a diminished level of antigenic and functional C1INH. Patients with Type II defects have sufficient protein, but one allele produces dysfunctional protein. We have sequenced the DNA from HAE patients and have discovered four previously unreported mutations. The first mutation is a splice site error at nucleotide 8721, which changes the 3' acceptor splice site AG to GG at the end of intron 5 at nucleotide 8721-8722. The second mutation is a single base insertion in exon 3 between nucleotides 2467 and 2468. The third mutation is a missense error present in the eighth exon of the C1INH; at nucleotide 16867 (amino acid 470), a T to A mutation transforms a Met to a Lys. The fourth mutation closely resembles the third mutation in that it is a missense error occurring in exon 8 in the distal hinge region; a T16827C substitution changes the Phe at amino acid 457 to Leu. This report compiles a list of 97 distinct defects in the C1INH gene that cause hereditary angioedema.

Amino Acid Substitution↗